Recent trials spotlight herpes, BV, and labor-related neutrophilia
Over the past few years, research in obstetric and gynecologic infectious diseases has led to improvements in diagnosis and management. Notable advances have been made in preventing group B streptococcus, sexually transmitted diseases, and postoperative pelvic infection.
Despite these successes and the development of broad-spectrum antibiotics, infection remains a serious cause of morbidity and mortality.
This update focuses on 3 studies from the past year:
- A randomized, controlled trial of famciclovir to suppress shedding of recurrent anogenital herpes simplex in women with and without symptoms,
- A randomized, controlled trial of metronidazole versus placebo in gravidas with asymptomatic bacterial vaginosis (BV), and
- The first non-observational investigation that explains the effects of labor on maternal neutrophil phenotype.
Using famciclovir to suppress shedding of recurrent anogenital herpes
Sacks SL. Famciclovir suppression of asymptomatic and symptomatic recurrent anogenital herpes simplex virus shedding in women: a randomized, double-blind, doubledummy, placebo-controlled, parallel-group, single-center trial. J Infect Dis. 2004;189:1341–1347.
- LEVEL I EVIDENCE: RANDOMIZED, CONTROLLED TRIAL
This well-designed study explored this question: Does famciclovir, administered thrice daily in an oral dose of 125 mg or 250 mg for 16 weeks, suppress symptomatic and asymptomatic shedding of herpes simplex virus? The answer is yes—an important finding since about 45 million people in the United States have genital herpes, and the number seems likely to continue rising. Asymptomatic viral shedding is believed to be the major risk factor in transmission and acquisition of herpes simplex.
In this study, 169 women with frequently recurring, culture-proven, genital herpes simplex infection were randomized to famciclovir 125 mg, 250 mg, or placebo. Patients kept a daily diary of any symptoms, and each morning performed self-sampling from as high in the vagina as possible, with a second sample taken from external genitalia. This involved swabbing the mons pubis, clitoral hood, labia minora, labia majora, perineum, and the perianal area. Data were analyzed with appropriate statistical tests.
A significant reduction in asymptomatic viral shedding occurred with famciclovir treatment, compared with placebo (P<.0001), while reduction of viral shedding in symptomatic women was dose-dependent: 0.72% for 125 mg versus 0.19% for 250 mg (P<.0001) versus 5.53% for placebo (P<.0001).
This study is notable because viral shedding was reduced in both symptomatic and asymptomatic women. It also opens the door for studies in pregnant women known to have herpes, with the aim of reducing the risk of perinatal transmission.
Does metronidazole eliminate BV in asymptomatic gravidas?
Klebanoff MA, Hauth JC, MacPherson CA, et al. Time course of the regression of asymptomatic bacterial vaginosis in pregnancy with and without treatment. Am J Obstet Gynecol. 2004;190:363–370.
- LEVEL II-1 EVIDENCE: NONRANDOMIZED, CONTROLLED TRIAL
In this trial, “asymptomatic” gravidas at 16 to 23 weeks’ gestation, who were diagnosed with BV by Gram stain, were randomized to two 2-g doses of oral metronidazole or placebo 48 hours apart. Two or more weeks after treatment, at the next regularly scheduled prenatal visit, the women were reevaluated for changes in the Gram stain score, with a median time to follow-up of 6.7 weeks.
Resolution of BV was defined as a Nugent’s score of less than 7, and restoration of the normal vaginal microflora was defined as a score of less than 4. Overall, 72% and 55% of women in the metronidazole group had scores of less than 7 and less than 4, respectively, at follow-up. In the placebo group, these percentages were 21% and 11%, respectively.
Like most studies of BV, this one is flawed. The reason: Rather than conduct quantitative bacteriology, investigators used the Gram stain to interpret the microbiology of an ecosystem and then related it to a significant medical outcome: preterm birth. They attempted to define BV as an infectious disease and applied principles of infectious disease treatment to it. Most investigators define BV as an alteration in the endogenous microflora, specifically a flora dominated by obligate anaerobic bacteria. However, they treat it as an infection and administer an antibiotic to correct the alteration in the vaginal ecosystem.
Questions raised by this study include: How is asymptomatic BV defined? Is it truly asymptomatic, or have patients simply adapted to their condition? Do these patients have abnormal discharge in color, quantity, and odor?
In addition, the lack of definitive bacteriology in this study necessitates the following assumptions:
- All BV is similar; therefore, similar responses to antimicrobial therapy should be expected.
- A score below 7 but above 4 represents intermediate flora. This microflora is a precursor to BV or predisposes the patient to BV infection.
- A score below 4 represents Lactobacillus-dominant flora.
In truth, intermediate flora based on the Gram stain is a vague category. Without quantitative bacteriology, it remains unclear whether a shift has occurred in the microflora that leads to dominance by a facultative anaerobic bacterium or bacteria. A score below 4 is similarly vague. Without quantitative bacteriology, it is impossible to determine whether the flora is dominated by Lactobacillus. Moreover, it is necessary to determine the species of Lactobacillus present to confirm that it is the correct species to reestablish normal microflora.
Investigators did demonstrate a fact seen in most treatment studies: Metronidazole is not a particularly good agent for treating BV and restoring a patient’s vaginal ecology to Lactobacillus-dominant flora. However, they failed to demonstrate that treatment of asymptomatic BV reduces the risk of preterm delivery in a general obstetric population, or to establish a causal relationship between BV and preterm labor. This did not prevent them from asserting the idea that BV is a risk factor for preterm labor.
Investigators clouded their findings further by concluding that two 2-g doses of metronidazole administered 48 hours apart were effective in 72% of cases (defined as the elimination of BV) and 55% effective in restoring Gram stain scores to the normal range, noting that this effect lasted 2 to 10 weeks or longer. In reality, this is neither elimination of BV nor restoration of a normal range of microflora, but simply an interpretation of the change in Gram stain characteristics. The results do not explain what is happening microbiologically; nor do they clarify the host response to these changing conditions. Intensive quantitative bacteriology is needed, along with research into the microbial ecopathophysiology and host response to specific bacteria, in patients with and without healthy vaginal flora.
It is important to understand vaginal microflora because, when it is altered, it can impact negatively on the patient’s health. Therefore, studies that elucidate the vaginal ecology and the relationships between various bacteria further our understanding of the microbial pathophysiology leading to infection. This, in turn, leads to development of preventive measures, thus reducing the risk for adverse outcomes in both the obstetric and gynecologic patient—especially those undergoing operative procedures.
Is labor inherently protective against infection?
Molloy EJ, O’Neill AJ, Grantham JJ, et al. Labor induces a maternal inflammatory response syndrome. Am J Obstet Gynecol. 2004;190:448–455.
- LEVEL II-3 EVIDENCE: MULTIPLE OBSERVATIONS WITH OR WITHOUT INTERVENTION; UNCONTROLLED STUDIES
This study probed the effect of labor on maternal neutrophil phenotype, concluding that labor primes the neutrophil—it enhances the antibacterial activity of the neutrophil, delays apoptosis of the neutrophil, and possibly promotes neutrophilia in women who deliver vaginally as well as those who deliver by cesarean section after labor.
Although the number of participants was relatively small, this study was well considered and constructed, investigating several immunologic responses in 5 groups of patients:
- 15 nonpregnant healthy women and 17 healthy men,
- 15 healthy women in labor at term before delivery,
- 9 women with normal term pregnancies before elective cesarean with no labor,
- 9 women before emergency cesarean section after partial labor, and
- 9 women at term before emergency cesarean section without labor.
Investigators found an increase in neutrophils and a delay of apoptosis in women who labored but not in those who didn’t. They also showed that introduction of the lipopolysaccharide delayed apoptosis of neutrophils regardless of the mode of delivery.
Interestingly, researchers also observed an increase of CD11b, an adhesion molecule and marker for neutrophil activation. Increased CD11b results in greater neutrophil activity.
Investigators concluded that the rise in neutrophils and diminished apoptosis in laboring patients may be an immunologic response to potential infection associated with labor, and that this phenomenon appears to be an inherent host reaction to prevent infection. It is known that bacteria from the genital tract of laboring women ascend into the uterus and amniotic fluid and colonize the decidua, amniotic membranes, and amniotic fluid. Women subsequently delivered by cesarean section are at a greater risk of infection than women delivered vaginally.
This is an extremely important finding and the first non-observational study to explain the rise in white blood cell counts during labor. It begins to explain the differences in white blood cell counts between laboring and nonlaboring patients and should spawn further investigations of a significant problem: postpartum endometritis.
Dr. Faro reports no financial relationships relevant to this article.